The present invention relates to a stent to be implanted in a stenotic lesion or occluded lesion of a lumen in a living body so as to maintain the stenotic lesion or occluded lesion in an open state. More particularly, the invention relates to a stent capable of releasing sustainedly, or little by little over a long period of time, a biologically/physiologically active substance or substances from a surface of the stent.
In recent years, a medical device called stent for treating a stenotic (constricted) lesion generated in a lumen in a living body, such as blood vessel, bile duct, trachea, esophagus, urethra, etc. has been used. A stent is a hollow tubular medical device which can be implanted in a stenotic lesion or occluded lesion of a lumen such as blood vessel for expanding the stenosis or occluded lesion and maintaining the lumen in an open state, for the purpose of treating a variety of diseases generated by stenosis or occlusion of lumens.
For example, in the case of the coronary artery, a stent is used for preventing the restenosis after percutaneous transluminal coronary angioplasty (PTCA).
By implanting the hollow tubular medical device called stent in a blood vessel after a surgical operation, it has been succeeded to lower the percentages of acute blood vessel occlusion and restenosis. Even where stents have been used, however, it has been recognized by a follow-up after half year and the like that restenosis would occur at the stent implanting lesion in an average ratio of around 20%. Thus, the problem of restenosis is still left to be solved.
Recently, a number of trials have come to be proposed in which a biologically/physiologically active substance such as a carcinostatic agent is loaded on the stent, and the biologically/physiologically active substance is released sustainedly and locally at the lesion where the stent is implanted, in order to lower the percentage of restenosis. For example, a stent in which a surface of a stent main body is coated with a mixture of a therapeutic substance and a polymer has been proposed in JP 8-33718 A. JP 8-33718 A describes a method of manufacturing the stent in which a solution composed of the polymer, the therapeutic substance, and a solvent is applied to the stent main body and then the solvent is evaporated off. In JP 8-33718 A, however, although it is described that the proposed stent is capable of sustainedly release the therapeutic substance and that the therapeutic substance includes both a solid therapeutic substance and a liquid therapeutic substance, it is not investigated to perform sustained release of different therapeutic substances with a large time lag therebetween. According to JP 8-33718 A, therefore, the therapeutic substances which are different from each other are released in substantially the same period. Besides, in the case of sustained release of a therapeutic substance which is extremely toxic to cells such as a carcinostatic agent, it is desirable to sustainedly release the therapeutic substance locally and a number of times, in a small amount at a time, from the viewpoint of suppression of side effects. However, designing of such a sustained therapeutic substance release is very difficult to achieve with the stent proposed by JP 8-33718 A.
JP 5-502179 A describes a stent in which medicaments for restricting occlusion of a blood vessel or the like are contained respectively in two or more polymer layers, and the medicaments are released with a time lag therebetween, wherein the polymer constituting each of the polymer layers is a bio-absorptive polymer. However, such a stent has the problem that, since a number of coating steps are required for forming the respective polymer layers, the manufacturing process is laborious and there would be large scattering among the individual stents manufactured. In addition, the total thickness of the polymer layers is large, which may impair the operating properties of the stent including its capability to reach the lesion.
On the other hand, biodegradable microspheres containing cisplatin therein are manufactured by a solvent evaporation process and are used for drug delivery system and the like (see G. Spenlehauer; M. Vert; J. P. Benoit; F. Chabot; M. Veillard, BIODEGRADABLE CISPLATIN MICROSPHERES PREPARED BY THE SOLVENT EVAPORATION METHOD: MORPHOLOGY AND RELEASE CHARACTERISTICS, “Journal of Controlled Release”, Elsevier Science Publishers B. V., Amsterdam, 1988, 7, pp. 217-229).